In this work, gliadin/sodium carboxymethyl cellulose nanoparticles (G/CMC) were prepared to encapsulate bioactive phloretin (Phl) for improving the stability and bioaccessibility by simple antisolvent precipitation. Scanning electron microscopy (SEM) and dynamic light scattering showed that G/CMC nanoparticles were spherical with the diameter below 350 nm. Electrostatic interaction and hydrogen bond were dominant driving force during the formation of G/CMC nanoparticles. Phloretin-loaded G/CMC nanoparticles (G/CMC-Phl) had robust resistance to pH shift, heat treatment and UV irradiation. The bioaccessibility of encapsulated phloretin increased from 23% to 55% via the strategy, as compared with free phloretin. Meanwhile, G/CMC-Phl had a strongly protective effect on erythrocyte hemolysis induced by 2, 2′-azobis-2-methyl-propanimidamide dihydrochloride (AAPH), and inhibited the generation of reactive oxygen species (ROS). It could recover the intracellular antioxidant enzymes (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) activity to normal levels and inhibit the production of malondialdehyde (MDA). Moreover, the protection and control release behavior of G/CMC nanoparticles was investigated by B16 mouse melanoma cells. This study provides a simple way to fabricate food-grade nanoparticles for the encapsulation of water-insoluble phloretin to broaden the application in pharmaceutical, cosmetics and food industry.